Controlled release of antibiotics has been studied all around the world for use in both systemic and local applications. The rate of release from a carrier system for a wide variety of diseases or infections depends on many factors including carrier solubility, acid-base relationships, structure and porosity of the carrier, mixed carriers of different solubilities to control or extend release rates of the mixture, etc. These are all based on short term release that is usually on days or weeks of release, not on long term protection. Release typically starts at a high concentration and falls off exponentially with time and/or is parabolic with time. Bacteria are constantly evolving so some strains in the mixture will have lower minimum effective concentrations than others. At some point the concentration will fall below the therapeutic level such that those with the low minimum effective concentration will be inhibited but those with the higher minimum effective concentration will survive. The slow rate of antibiotic release below the lower minimum effective release concentration allows the most resistant strains to survive and multiply leading to the development of antibiotic resistant bacteria. High local concentrations of antibiotics are often used but their activity is gone as soon as they are dissipated.
All implants used in surgical repair under load-bearing conditions are walled off by the patient's foreign body response. Examples include, but are not limited to, metals such as 310-L stainless steel, cobalt chrome alloys, titanium alloys; aluminum oxide; polyethylene and polymethylmethacrylate. Local infections sometimes occur after surgery, either from sepsis during surgery or by localization of systemic infections after surgery. For example, Staphylococcus aureus may produce a biofilm on the surface of implants that acts as a barrier which prevents antibiotics at systemic levels from curing the infection. Endotoxins are released from Gram-negative bacteria when undergoing autolysis. The endotoxins invoke inflammatory response including local reduction of pH. Resorption of tissue often accompanies these infections.
Many infections associated with orthopedic implants which are difficult to treat systemically are classified as Gram-negative bacteria. They have a tough outer capsule that is resistant to antibiotic penetration. They can secrete cytokines and induce toxic immune responses such as endotoxins. They induce the tissue inflammatory response such as proliferation of monocytes, macrophages, fibroclasts, and osteoclasts that lysis proteins, connective tissue and bone by lowering the pH or by humoral components. This cause redness, swelling and pain and results in resorption of tissue, including bone.
Using orthopedic surgery as an example, but not to exclude other surgical procedures, joint replacements, such as knees or hips, are plagued by “deep infections” where a local infection occurs at the implant site that cannot be cured by systemic antibiotics. About 750,000 knee and hip implants are implanted each year in the United States. About 2% experience deep infection. These are very painful and are accompanied by inflammatory responses that can cause bone resorption and loosening of the implant. This requires removal of the implant, use of systemic antibiotics to cure the infection and allow healing that may require several months, followed by revision surgery to insert a new joint implant. Revision surgeries are more difficult than primary surgeries. There are many other examples such as infection accompanying an open fracture, osteomyelitis, spinal and oral facial surgery.
Other examples occur in dentistry. For example, root canals are required when a tooth becomes infected. If the root canal does not control the infection, the tooth must be removed. Crowns on teeth are cemented in place with luting cement. If the exposed cement at the margins is eroded and caries occurs under the crown, the crown must be removed, the caries damage repaired, a new restoration prepared, and a new crown placed. If periodontal disease occurs sufficient to require debridement of the tooth/or bone, local antibiotics are often administered to prevent re-infection. This may not be successful and the tooth may need to be removed. These examples show the need for a local antibiotic that will be released if infection occurs. There is an urgent need to prevent and/or control local infections in soft and hard tissues.
In studying the mechanisms of tissue response to implants, fluorescent labels may be used to analyze the healing process. Using bone as an example, not to exclude other applications, the fluorescent label is a dye that can be given at a specific time that is absorbed by the bone only at sites where new bone is forming. More than one label can be used at specific times. Then, when the specimen is recovered, sections can be cut from the site of interest and examined with a fluorescent microscope. Each color of fluorescent dye can be visualized so that the precise areas where new bone was forming at the time the dye was given can be mapped. And the spacing between each dye can be used to determine the rate that the bone was forming. This is a powerful tool for understanding bone formation and tissue response.
The tetracycline family of antibiotics is very extensive, all based on four fused hexagonal “Rings” in a linear array, generally in a linear planar construction. When tetracycline was introduced as an antibiotic in the 1940s, it was a wonder drug, broad spectrum to inhibit growth of many bacteria whether gram negative or gram positive, and even inhibited rickettsia diseases like Rocky Mountain Scarlet Fever. There were only about three variants but bacterial resistance developed. Many variations of tetracycline have been developed to improve performance. But the resistant strains have limited its use. The simplest form is shown in Diagram 1 as a planar molecule. The rings are labeled A B C D and the branches off the rings appear to be in the plane also. Actually, in the three dimensions the branches are kinked so that extensions off the A ring look like bent thumb and index fingers. The spacing is steric (correct geometry) for chelating a calcium ion (as though the ion was caught in the fingers grasp). This is held tightly as a strong chemical bond composed of steric, covalent and ionic components. When this happens the molecule is no longer effective as an antibiotic. The bond is difficult to break.
The original tetracycline was infused (welcomed into) bacteria cells where it interfered with the ribosomes that manufacture proteins for cell multiplication. Resistance by bacteria includes modifications that pump the tetracycline out of the cell before it can interfere with the protein manufacture; or modify the ribosome RNA to allow manufacture of proteins in the presence of tetracycline.

Ciprofloxacin is a member of the quinolone family of drugs. Early quinolones were not as effective as the fluoroquinolones. Ciprofloxacin is a second-generation fluoroquinolone antibiotic that had a wide spectrum of applications in clinical use in the 1980s and 1990s. In 2000 it was the fifth most commonly prescribed drug in the U.S. Increased resistance and the structure of the molecule (Diagram 2) allow many variants to be investigated. In general the improved drugs avoid some of the mechanisms for antibiotic resistance and research is still being conducted. There are now thousands of derivatives.
Ciprofloxacin prevents bacteria growth by targeting two essential bacterial enzymes, DNA gyrase and DNA topoisomerase IV that are essential to cell reproduction. The quinolones bond to aluminum ions by a chelating complex similar to the bonding of calcium ions to tetracycline described above. The bond is very stable and prevents antibiotic activity.
